Design and Development of Halogenated Chalcone Derivatives as Potential Anticancer Agents

Purpose: To design and develop halogenated chalcone derivatives and evaluate them as anticancer agents using different cancer cell lines.Methods: Based on in silico design and docking on known target, crystal structure of the complex of interleukin-1beta converting enzyme (ICE) with a peptide based inhibitor, (3S )-N-Methanesulfonyl-3- ({1-[N-(2-naphtoyl)-l-valyl]-l-prolyl}amino)-4-oxobutanamide (1BMQ), novel halogenated chalcone derivatives were designed (7a-h) employing LigandFit module of Accelrys (Discovery Studio, 2.1 version). Standard protocols for ligand and protein preparation were employed and their binding orientation validated using (3S)-N-Methanesulfonyl-3-({1-[N-(2-naphtoyl)-l-valyl]-l-prolyl}amino)-4-oxobutanamide (MNO 601), a caspase inhibitor as reference standard. Energy minimized conformers with best dock scores were considered for the identification of interacting amino acid residues with ligands. Selected derivatives were synthesized and analyzed by melting point, 1H NMR, IR and mass spectroscopy. Their evaluation for anticancer activity was carried out using adriamycin, paclitaxel and 5-fluorouracil as reference standards on prostrate (PC-3), colon (COLO-205), ovary (OVCAR-5), liver (HEP-2) and neuroblastoma (IMR-32) cancer cell lines, and % growth inhibition and half maximal inhibitory concentration (IC50) values were calculated.Results: Among synthesized compounds, 7b showed the most promising cytotoxic activity with an IC50 of 49.9 ìM on colon cancer cell lines (Colo-205), followed by 7d with an IC50 of 66.6 ìM against ovarian cancer cell lines (OVCAR-5).Conclusion: We report the successful synthesis, spectral characterization and in vitro anticancer evaluation of a series of novel halogenated chalcone derivatives against a number of human cancer cell lines. The findings indicate the emergence of new anticancer compounds.Keywords: Halogenated chalcones, Dock scores, Anticancer activity,  Interleukin-1beta converting enzyme

Probing Density Fluctuations using the FIRST Radio Survey

We use results of angular clustering measurements in 3000 sq. deg's of the FIRST radio survey to infer information on spatial clustering. Measurements are compared with CDM-model predictions. Clustering of FIRST sources with optical ID's in the APM catalog are also investigated. Finally, we outline a preliminary search for a weak lensing signal in the survey.Comment: 6 pages latex, 2 figures, to appear in Cosmology with the New Radio Surveys (Kluwer

Deposition of Smoke Particles in Human Airways with Realistic Waveform

Exposure to toxic particles from smoke generated either from bush fire, stable burning, or direct smoking is very harmful to our health. The tiny particles easily penetrate deep into the lungs after exposure and damage the airways. Tobacco smoking causes the direct emission of 2.6 million tons of CO2 and 5.2 million tons of methane annually into the atmosphere. Nevertheless, it is one of the significant contributors to various respiratory diseases leading to lung cancer. These particles’ deposition in the human airway is computed in the present article for refining our understanding of the adverse health effects due to smoke particle inhalation, especially cigarette smoke. Until recently, little work has been reported to account for the transient flow pattern of cigarette smoking. Consideration of transient flow may change the deposition pattern of the particle. A high-resolution CT scan image of the respiratory tract model consisting of the oral cavity, throat, trachea, and first to sixth generations of the lungs helps predict cigarette smoke particle (CSP) deposition. With the same scan, a realistic geometric model of the human airways of an adult subject is used to simulate the transport of air and particle. The CSP deposition is determined at different locations from the oral cavity to the sixth generation of the bronchi. In addition, an unsteady breathing curve indicative of realistic smoking behavior is utilized to represent the breathing conditions accurately. The discrete phase model (DPM) technique is used to determine smoke particle deposition in the human airways. It is found that the deposition increases with the size of the smoke particle. Particles tend to deposit in the oral cavity around the bifurcation junction of the airways. The deposition fraction of CSP with the realistic waveform of smoking is found to be smaller compared to that during the stable flow condition. It is also observed that the fine particles (0.1–1.0 micron) escape to lower generations, leading to higher deposition of fine particles in the deeper airways. The outcome of the study is helpful for understanding smoke-related pulmonary complications

Developing Crisis Training Software for Local Governments – From User Needs to Generic Requirements

In this paper we analyze and present the generic requirements identified for a software aiming at supporting crisis management training in local governments. The generic requirements are divided into overall requirements, requirements connected to the trainer’s role and requirements connected to the trainee’s role. Moreover, the requirements are mapped to problems as well as opportunities. Finally, we present examples of elaborations of the addressed requirements based on software design considerations. In our work we applied a design science approach and the artifact presented in this paper is a list of generic requirement. The presented requirements and the systems development process used, provide guidelines for systems analysts and developers in future systems development projects aiming at constructing new software for crisis management training

Evaluation of a Bayesian inference network for ligand-based virtual screening

Background Bayesian inference networks enable the computation of the probability that an event will occur. They have been used previously to rank textual documents in order of decreasing relevance to a user-defined query. Here, we modify the approach to enable a Bayesian inference network to be used for chemical similarity searching, where a database is ranked in order of decreasing probability of bioactivity. Results Bayesian inference networks were implemented using two different types of network and four different types of belief function. Experiments with the MDDR and WOMBAT databases show that a Bayesian inference network can be used to provide effective ligand-based screening, especially when the active molecules being sought have a high degree of structural homogeneity; in such cases, the network substantially out-performs a conventional, Tanimoto-based similarity searching system. However, the effectiveness of the network is much less when structurally heterogeneous sets of actives are being sought. Conclusion A Bayesian inference network provides an interesting alternative to existing tools for ligand-based virtual screening

Prolonged gastroparesis after corrective surgery for Wilkie's syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Wilkie's syndrome, a rare cause of intestinal obstruction, is related to anatomical and mechanical factors associated with the reduction of retroperitoneal fat padding. The diagnostic challenges of identifying vascular constriction between the aorta and superior mesenteric artery have been answered by advances in the field of computed tomography. Despite diagnostic confusion with intestinal dysmotility syndrome, conservative therapy with nutritional supplementation is the initial approach and duodenojejunostomy is favoured if non-surgical treatment fails.</p> <p>Case presentation</p> <p>We present a case of a 49-year-old woman with Wilkie's syndrome with persistent symptoms of gastroparesis for 15 months following corrective surgery.</p> <p>Conclusion</p> <p>Open and laparoscopic duodenojejunostomy have been described as the best surgical treatment options for Wilkie's syndrome, but further work needs to be done for patients with refractory symptoms of gastroparesis after these corrective surgeries.</p

A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: Intermediate-term results

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA+LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 ± 1.3 vs 2.3 ± 1.8 years; p < 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA+LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA+LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n = 1) and methotrexate therapy (n = 1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation

Lipocalin-7 Is a Matricellular Regulator of Angiogenesis

Matricellular proteins are extracellular regulators of cellular adhesion, signaling and performing a variety of physiological behaviors such as proliferation, migration and differentiation. Within vascular microenvironments, matricellular proteins exert both positive and negative regulatory cues to vascular endothelium. The relative balance of these matricellular cues is believed to be critical for vascular homeostasis, angiogenesis activation or angiogenesis resolution. However, our knowledge of matricellular proteins within vascular microenvironments and the mechanisms by which these proteins impact vascular function remain largely undefined. The matricellular protein lipocalin-7 (LCN7) is found throughout vascular microenvironments, and circumstantial evidence suggests that LCN7 may be an important regulator of angiogenesis. Therefore, we hypothesized that LCN7 may be an important regulator of vascular function.To test this hypothesis, we examined the effect of LCN7 overexpression, recombinant protein and gene knockdown in a series of in vitro and in vivo models of angiogenesis. We found that overexpression of LCN7 in MB114 and SVEC murine endothelial cell lines or administration of highly purified recombinant LCN7 protein increased endothelial cell invasion. Similarly, LCN7 increased angiogenic sprouting from quiescent endothelial cell monolayers and ex vivo aortic rings. Moreover, LCN7 increased endothelial cell sensitivity to TGF-β but did not affect sensitivity to other pro-angiogenic growth factors including bFGF and VEGF. Finally, morpholino based knockdown of LCN7 in zebrafish embryos specifically inhibited angiogenic sprouting but did not affect vasculogenesis within injected embryos.No functional analysis has previously been performed to elucidate the function of LCN7 in vascular or other cellular processes. Collectively, our results show for the first time that LCN7 is an important pro-angiogenic matricellular protein of vascular microenvironments

Massive retroperitoneal tubercular abscess mimicking a leaking abdominal aortic aneurysm: a case report

In spite of being a common diagnosis in the patients of Asian origin, atypical presentations of tuberculosis may pose diagnostic challenges. We report a huge prevertebral abscess in a 30-year-old female, mimicking a leaking aortic aneurysm. The patient was managed successfully by emergency decompression and stabilization. The issues related to poor patient compliance to chemotherapy and management of atypical presentations of spinal tuberculosis are discussed here